Two tagging single-nucleotide polymorphisms to capture HLA-DRB1*07:01–DQA1*02:01–DQB1*02:02 haplotype associated with asparaginase hypersensitivity

Abstract

Aims: Asparaginase (ASP) hypersensitivity is a well-known challenge in the treatment of lymphoblastic malignancies. In terms of cost considerations, the cheap native Escherichia coli ASP, the most immunogenic form of this medication, is used in the first line in middle-income countries. Previously, the role of the HLA-DRB1*07:01–DQA1*02:01–DQB1*02:02 haplotype had been established to associate with E. coli ASP hypersensitivity. We investigated a possible cost-effective genetic testing method to identify patients harbouring the risk HLA haplotype in order to pave the way for safer ASP treatment. Methods: In 241 patients with previously determined HLA-DRB1*07:01–DQA1*02:01–DQB1*02:02 haplotype and known ASP hypersensitivity status, 4 candidate HLA-tagging single-nucleotide polymorphisms (SNP)s were measured, and the performance of the different sets of these tag SNPs was evaluated. Results: We identified a combination of 2 SNPs — rs28383172 and rs7775228 — as a tag for HLA-DRB1*07:01–DQA1*02:01–DQB1*02:02 haplotype with sensitivity and specificity values >95%. In line with previous findings, we found complete concordance between HLA-DRB1*07:01 and rs28383172. With bioinformatics methods, the results were also confirmed in the 1000 Genomes dataset in different ethnic groups. Conclusion: Rs28383172 and rs7775228 are suitable for identifying HLA-DRB1*07:01–DQA1*02:01–DQB1*02:02 carriers. Compared to the rest of the population, patients with hypersensitivity-prone genotype would benefit more from the administration of less immunogenic PEGylated ASP before the hypersensitivity evolves, incurring minimal extra cost.